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J. Biol. Chem., Vol. 283, Issue 47, 32452-32461, November 21, 2008

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Structural and Biochemical Characterization of the Oxidoreductase NmDsbA3 from Neisseria meningitidis^*

Julian P. Vivian¹², Jessica Scoullar¹, Amy L. Robertson, Stephen P. Bottomley, James Horne^¶, Yanni Chin^¶, Jerome Wielens^¶, Philip E. Thompson^¶, Tony Velkov^¶, Susannah Piek, Emma Byres, Travis Beddoe³, Matthew C. J. Wilce, Charlene M. Kahler, Supported by grants from the Ada Bartholomew Medical Research Trust and the Medical and Health Research Infrastructure Fund of Western Australia⁴⁵, Jamie Rossjohn, Supported by an ARC Federation Fellowship⁴⁶, and Martin J. Scanlon^¶47

From the The Protein Crystallography Unit, ARC Centre of Excellence in Structural and Functional Microbial Genomics, School of Biomedical Sciences, Monash University, Clayton, Victoria 3800, the School of Biomedical, Biomolecular & Chemical Sciences, QEII Medical Centre, University of Western Australia, Crawley, Western Australia 6009, and the ^¶Medicinal Chemistry and Drug Action, Monash Institute of Pharmaceutical Sciences, Monash University (Parkville Campus), 381 Royal Parade, Parkville, Victoria 3052, Australia

DsbA is an enzyme found in the periplasm of Gram-negative bacteria that catalyzes the formation of disulfide bonds in a diverse array of protein substrates, many of which are involved in bacterial pathogenesis. Although most bacteria possess only a single essential DsbA, Neisseria meningitidis is unusual in that it possesses three DsbAs, although the reason for this additional redundancy is unclear. Two of these N. meningitidis enzymes (NmDsbA1 and NmDsbA2) play an important role in meningococcal attachment to human epithelial cells, whereas NmDsbA3 is considered to have a narrow substrate repertoire. To begin to address the role of DsbAs in the pathogenesis of N. meningitidis, we have determined the structure of NmDsbA3 to 2.3-Å resolution. Although the sequence identity between NmDsbA3 and other DsbAs is low, the NmDsbA3 structure adopted a DsbA-like fold. Consistent with this finding, we demonstrated that NmDsbA3 acts as a thiol-disulfide oxidoreductase in vitro and is reoxidized by Escherichia coli DsbB (EcDsbB). However, pronounced differences in the structures between DsbA3 and EcDsbA, which are clustered around the active site of the enzyme, suggested a structural basis for the unusual substrate specificity that is observed for NmDsbA3.

Received for publication, May 26, 2008 , and in revised form, July 18, 2008.

The atomic coordinates and structure factors (code 2ZNM) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

^* This work was supported in part by Australian Research Council (ARC) Grant LP0455508 and National Health and Medical Research Council (NHMRC) Grant 455860. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Both authors contributed equally to the work.

² Supported by a Peter Doherty Fellowship from the NHMRC.

³ Supported by a NHMRC Career Development Award.

⁴ Co-senior authors.

⁵ To whom correspondence may be addressed. E-mail: ckahler{at}cyllene.uwa.edu.au. ⁶ To whom correspondence may be addressed. E-mail: Jamie.rossjohn{at}med.monash.edu.au. ⁷ To whom correspondence may be addressed. E-mail: Martin.Scanlon{at}pharm.monash.edu.au.

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